Dehydroepiandrosterone (DHEA), also known as 3-beta-hydroxyandrost-5-en-17-one, dehydroisoandrosterone, trans-dehydroandrosterone, Δ5-androsten-3-β-ol-17-one, and prasterone, is a naturally occurring intermediate formed in the course of synthesis of various steroids from cholesterol. DHEA is the most abundant steroid hormone in humans and is produced mainly by the adrenal cortex as an inactive sulfate ester (DHEA-S). DHEA production also occurs in the testes, ovaries, and brain. After achieving a plateau level during early adulthood (ages 16 to 24), total serum DHEA (DHEA+DHEA-S) declines steadily to about 5 to 10% of peak values by age 60 to 70 (Orentreich et al., 1984).
DHEA has been proposed for use in treating many medical conditions, such as systemic lupus erythematosus (U.S. Pat. No. 5,817,650), primary adrenal insufficiency (U.S. Pat. No. 5,861,391), Addison's disease (ibid.), reduced libido (U.S. Pat. No. 5,855,548), obesity (U.S. Pat. No. 5,846,962), osteoporosis (U.S. Pat. Nos. 5,846,960 and 5,855,548), and fibromyalgia (U.S. Pat. No. 5,935,949). DHEA can be administered by various routes and is orally active.
The pharmacokinetics of exogenously administered DHEA are complicated by endogenous production of DHEA and by the reversible interconversion between DHEA and DHEA-S, the major metabolite of DHEA, which acts as a reservoir for DHEA. DHEA exhibits wide diurnal variations in endogenous production, while DHEA-S levels show little variation during the day. Changes in plasma DHEA occur in parallel to those of ACTH and cortisol, with an early morning maximum, declining levels through the daytime, and minimal secretory activity in the early part of the night (van Cauter, 1990; Lacheline et al., 1979; Yen et al., 1995).
Both DHEA and DHEA-S are bound by serum albumin, globulins, and steroidal sex hormone binding globulin (Meikle et al., 1992; Longcope, 1995). Only a small fraction of orally administered DHEA appears in the blood at any given time as DHEA; most undergoes conversion to DHEA-S by sulfotransferases in the liver and extrahepatic tissues (Barker, 1994; Corner, 1992; Falany, 1995; Arlt, 1998). DHEA-S is converted back to DHEA by peripheral tissues containing DHEA sulfatases, including lymphocytes and macrophages. DHEA is subsequently metabolized to androstenedione as well as the potent androgens, testosterone and dihydrotestosterone, and the estrogens, estrone and estradiol. Adipose tissue may serve as a substantial reservoir for adrenal androgens. The aromatization of DHEA in peripheral tissue is thought to account for the majority of estrogen biosynthesis in postmenopausal women (Grodin et al., 1973).
The bioavailability of a drug can play an important role in its efficacy. It has been reported that DHEA occurs in at least three and as many as five anhydrous polymorphic forms and at least three hydrated forms, depending on environmental conditions and the manner of preparation (Chang et al., 1995). The known forms have been reported to be distinguishable on the basis of infrared spectroscopy and powder diffraction analysis, except that forms S3 and S4 are indistinguishable using the latter method (ibid.). Work conducted in support of the present invention indicates the existence of a sixth anhydrate form designated herein as form VI, which is detectable by solid state NMR but not by infrared spectroscopy or x-ray powder diffraction analysis.
Although DHEA is available from a variety of commercial sources, these materials show significant variation in their polymorphic compositions, which can cause variations in bioavailability due to differences of absorption during uptake in vivo.
Accordingly, it is an object of the present invention to provide DHEA formulations enriched in the form I polymorph or the form II polymorph, to achieve more consistent bioavailability and reliable efficacy. Formulations enriched in the form VI polymorph are also contemplated.